Heterocyclic carboxylic acid esters of fluocinolone-acetonide

ABSTRACT

Novel esters of fluocinolone-acetonide or 6 Alpha ,9 Alpha -difluoro-16 Alpha ,17 Alpha -isopropylidenedioxy- Delta 1,4pregnadiene-11 Beta ,21-diol-3,20-dione of the formula   WHEREIN R is selected from the group consisting of pyridine-3, pyridine-4, benzofuran-2 or 1-menthoxymethyl having high glucocorticoid and antiphlogistic activity and their preparation.

United States Patent [1 1 Heider et' al.

June 19, 1973 HETEROCYCLIC CARBOXYLIC ACID ESTERS OF FLUOCINOLONE-ACETONIDE {30] Foreign Application Priority Data Feb. 4, 1970 Germany P 20 05 002.6

[52] US. Cl. 260/239.55 D, 424/241 [51] Int. Cl C07c 173/10 [58] Field of Search Machine Searched Steroids [56] References Cited UNITED STATES PATENTS 3,053,836 9/1962 Fried 260/239.S5

3,374,230 3/1968 Gardner et al 260/239.55

Primary ExaminerHenry A. French AttorneyHammond & Littell [57] ABSTRACT Novel esters of fluocinolone-acetonide or 6a,9a-difluoro- 1 6a,] 7a-isopropylidenedioxy-A" -pregnadienellB,2l-diol-3,20-dione of the formula O oxen; 0 CH1 wherein R is selected from the group consisting of pyridine-3, pyridine-4, benzofuran-Z or l-menthoxymethyl having high glucocortico'id and antiphlogistic activity and their preparation.

5 Claims, No Drawings blooded animals.

OBJECT'OF THE INVENTION It is an 'object of the invention to provide the novel esters of fluocinolorte-acetonide of formula I.

It is another object of the invention to provide a novel process for the preparation of the esters of formula I.

It is a further object of the invention to provide novel therapeutic compositions having high glucocorticoid and antiphlogistic activity.

It is an additional object of the invention to provide a novel method of reducing inflammation in warm- These and other objects and advantages of the invention will become obvious from the following detailed description.

THE INVENTION ,The novel esters of the invention have the formula cmofieoan with an acylating derivative of an acid selected from the group consisting of nicotinic acid, isonicotinic acid, benzo-2-furan carbonic acid and l-menthoxy-acetic acid at a temperature of to 90 to form the corresponding 21-acid ester of fluocinolone-acetonide. 'Iihe acylatingderivative may bean acid=halide, symmetrical or mixed acid anhydride or imidazolides.

The reaction is preferably carried-out in the presence of an inert organic solvent such as tetrahydrofuran, dimethylformamideor dioxane and optionally in the presence of a hydrogen halide binding agent, preferably in the presence ofatertiary amine such as pyridine. This amine may even be simultaneouslyused as-the, solvent. If an imidazolide of one of the mentioned acids is used, the reaction will proceed at room. temperature and produces a high yield especially if an imidazole saltis used as catalyst. It is not necessary to isolate the used boxylic acids if dicyclohexylcarbodiimide' is used as de-.

hydrating agent. This reaction isadvantageously carimidazolide. A solution of sulfmyl diimidazolide in an inert solvent obtained in known manner is preferably mixed with the corresponding acid and after approximately 30 minutes stirring, the fluocinolone-acetonide is added thereto.

The new compounds can also be obtained by reacting fluocinolone-acetonide with one of the mentioned carried out in 'a solvent such as pyridine or dioxane at room temperature or at elevated temperatures. The progress of the reaction can be checked in all cases by thin-layer chromatography. The crude product thus obtained may be purified for example, chromatographicall y, for instance over a silica gel column. 1

The novel glucocorticoid and antiphlogistic compositions of the invention are comprised of an effective amount of at least one ester of formula I and a major amount of a pharmaceutical carrier. The compositions may be in the form of aerosols, ointments, creams, tinctures, drops and suspensions. Topical preparations preferably contain 0.00125 to 0.125 percent, preferably 0.01 percent, by weight of the esters of formula I and individual systemic doses are 0.05 to 0.25 mg, preferably 0.125 mg, of the active ester of formula I. The

compositions may also contain other active ingredients I such as antibiotics, antihistamines and vasoconstrictive agents for use in eye drops or car drops, for example.

The novel method of .the'invention for reducing inflammation in warm-blooded animals comprises administering to warm-blooded animals an effective amount of an ester of formula I. The said esters can be administered topically or systemically, i.e., orally or transcutaneously. The usual daily systemic dose is 0.25 to 2.0 mg/kg. i

In the following-examples there are described several preferred embodiments to illustrate the invention. However, it shouldbe understood that the'invention is not intended to be limited to the specific embodiments.

EXAMPLE 1 Fluocinolo'ne-acetonide-Z l -isonicotinate 225 mg of fluocinolone-acetonide dissolved in 4 ml of pyridine and250 mg of isonicotinic acid anhydride dissolved in 4' ml of dioxane were mixed together and stirred for, four hours at room temperature. The progress of the reaction was checked by thin-layer chromatography. After pouringthe reaction solution into approximately 100ml of 3 percent ammonium chloride solution, the precipitate was filteredoff and dissolved in chloroform-. The solution wasdriedand evaporated to dryness and theresidue wasjrecrystallized from a methanol/water mixtureto obtain 260 mgm( percent of theory) of fluocinolone-acetonide-21-isonicotinate isonicotinoyloxy-Al "'-pregnadiene-1 l B-ol-3,20-dione in the form of white crystals melting at 250C (decomp.):

EX AMPLE Z Fluocinolone-acetonide -2-l -benzofuranate 225 mgm offluocinolone-acetonide dissolved in 2 ml of pyridine and 250 mgm of benzofuran-Z-carbonic acid chloride dissolved in 3 ml of dioxane were admixed and'stirred foro hours at room temperature. The course of the reaction was followed by thin-layer chromatography. After having poured the reaction solution into approximately 100 ml of 3 percent ammonium chloride solution, the precipitate was filtered off and subsequently dissolved in chloroform. The chloroform solution was dried and evaporated to dryness. The residue was recrystallized from methanol/water mixture to obtain 295 mgm (95 percent of theory) of fluocinolone-acetonide-Z 1 -ben z ofuranate or 6a,9a-difluoro- 16a,17a-isopropylidinedioxy-21-(benzofuran-2- carbonyloxy)-A"-pregnadiene-1lB-ol- 3,20-dione in the form of white crystals melting at 265 to 270C.

EXAMPLE 3 F1uocino1one-acetonide-2 1 -nicotinate 225 mgm of fluocinolone-acetonide dissolved in 4 ml of pyridine and 250 mgm of nicotinic acid and 500 mgm of dicyclohexylcarbodiimide dissolved in 4 ml of dioxane were mixed together and stirred at room temperature for 20 hours. The reaction mixture was further processed as described in Example 1 and subsequentlythe reaction mixture was purified chromatographically over a silicagel column (silicagel 0.2-0.5 mm; chloroformzmethanol 19:1, 9:1 and 7:1). The reaction product was recrystallized from a mixture of ether and hexane to obtain 160 mgm (53 percent of theory) of fluocinolone-acetonide-2l-nicotinate or 6a,9a9a-difluorol601,170:17a-isopropylidenedioxy-2l-nicotinoyloxy- A -pregnadiene-l 1B-ol -3,20-dione in the form of white crystals melting at 200203C.

EXAMPLE 4 Fluocinolone-acetonide-Z l-isonicotinate 0.15 ml of thionyl chloride was added dropwise to a solution of 400 mg of imidazole in ml of tetrahydrofuran and the precipitate of imidazole hydrochloride was vacuum filtered under a nitrogen atmosphere. 240 mg of isonicotinic acid were added to the filtrate and the mixture was shaken for 30 minutes. Then, 100 mg of fluocinolone acetonide and sodium imidazolide (catalyst) were added to the reaction mixture which was allowed to stand overnight. Thin-layer chromatography showed the reaction to be complete and the reaction mixture was then processed as in Example 1. The product was recrystallized from amethanol/water mixture to obtain 95 mg (67 percent of theory) of fluocinolone acetonide-2 l-isonicotinate or 60:, 9adifluoro- 1 6a,17a-isopropylidenedioxy-2lisonicotinoyloxy-Al- -pregnadiene-1 1 fl-ol-3,20-dione in the form of white crystals beginning to melt at 250C (decomp) 7 EXAMPLE 5 Fluocinolone-acetonide-2 1 -1-menthoxy-acetate 450 mg of fluocinolone-acetonide, 500 mg of 1men thoxyacetic acid and 500 mg of dicyclohexylcarbodiimide were dissolved in 5 ml of pyridine and the solution was heated on the steam bath for 5 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in acetone. The solution was filtered to remove dicyclohexylurea and the filtrate was purified over a silicagel column (0.2-0.5 mm) with chloroformzacetone 19:1, 9:1 and 7:1. The crude product was recrystallized from a 1:1 water/ethanol mixture to obtain 600 mg 92 percent of theory) of fluocinolone acetonide-Zl-menthoxy-acetate or 6a,9a-difluoro- 1601,1711 -isopropylidenedioxy-21 1-menthoxy acetoxy)- A "-pregnadiene-1lB-ol-3,20-dione in the form of white crystals melting at 202205C.

PHARMACEUTICAL EXAMPLES EXAMPLE A Metered aerosol inhalator composition: Composition:

1 Container of single doses contains:

Fluocinolone-acetonide-Z l -isonicotinate 0.625 mgm Chloropheniramine maleate V 62.5 2-(5,6,7,8tetrahydro-l-naphthylamino)-2- imidazoline l-lCl 15.0 Neomycin sulfate 12.5 Sorbitan trioleate 43.75 Chamomile oil 6.25 lsopropyl myristate 125.00 Trifluorotrichloroethane 64.375

Monofluorotrichloroethane/difluorodichloromethane/tetrafluuorodichloroethane 30 30: 40 8670.0

9000.0 mgm EXAMPLE B Metered aerosol inhalator Composition:

One container single doses) contains:

Fluocinolone acetonide-21-benzofuranate 3.75 mgm Sorbitan trioleate 37.5 Monofluorotrichloromethane 2648.05 Diflourodichloromethane/tetrafluorodichloroethane 10500.0 mgm Production:

Into a mixture of sorbitan trioleate and monoflourotrichloromethane was suspended micronized fluocinolone acetonide-2l-benzofuranate with an immersion homogenizer. This mixture was stirred into the propel- 'lant gas mixture cooled to -50C. At 50C the suspension was filled into metered aerosol containers. Immediately after filling, the containers was closed by a metering valve so that 0.025 mg of fluocinolone acetonide-2l-benzofuranate is dispensed in each dose.

EXAMPLE C Ointment Composition:

Fluocinolone-acetonide-Zlisonicotinate 0.01 gm Vaseline 20.0 Decyl ester of oleic acid 15.0 Cetyl alcohol 1.0 Wool wax alcohol 2.0 Sorbitan monooleate 4.0 Distilled water 57.99

100.0 grn Production: 1

Micronized fluocinolone-acetonide-2l-isonicotinate was suspended with an immersion homogenizer into the molten fatty phase cooled to 70C. Distilled water was heated to 70C and emulsified into the fatty phase. It was cooled to room temperature while stirring.

EXAMPLE D Cream with 0.01 percent of fluocinolon'e-acetonide-2l-benzofuranate, 0.3 percent of pimaricin, 0.2 percent of hexachlorophene, 0.01 percent of vitamin-A-acetate and 0.02 percent of vitamin-E-acetate Composition:

Flucinolone-acetonide-Z 1 -benzofuranate 0.01 gm Pimaricin 0.3 gm Hexachlorophene 0.2 gm Vitamin-A-acetate 0.01 gm Vitamin-E-acetate 0.02 gm Butylhydroxyanisol 0.1 gm Decyl ester of oleic acid 11.0 gm Cremophor O 4.4 gm Cetylstearyl alcohol 5.5 gm Sperm oil 3.3 gm Glycerin monostearate 4.4 gm Silicon oil AK 350 2.0 gm Perfume concentration a la Nivea 0.2 gm 70% Sorbitol 5.0 gm Citric acid 0.1 gm Disodium phosphate 2 H O 0.4 gm Distilled water 63.06 gm Production:

In a melt of decyl ester of oleic acid, Cremophor, cetylstearyl alcohol, sperm oil, glycerin monostearate and silicon oil were dissolved at 70C hexachlorophene, vitamin- A-acetate, vitamin-E-acetate and butylhydroxyanisol. Subsequently, the micronized fluocinolone-acetonide-Zl-benzofuranate and the micronized pimaricin were suspended with an immersion hmogenizer. Distilled water was heated to 70C and therein were dissolved citric acid, disodium phosphate and sorbitol. The oily suspension of the active ingredients was added to the aqueous phase while stirring at the indicated temperature. The resulting emulsion was homogenized and cooled to 45C. After addition of the perfume, the cream was degased and cooled to room temperature while stirring slowly.

EXAMPLE E Lotion with 0.01 percent of fluocinolone-acetonide-2l-isonicotinate Composition:

Fluocinolone-acetonide-Z 1 -is0nicotinate 0.01 gm Sorbitan monopalmitate 1.0 gm Cremophor O 2 0 gm, Cetylstearyl alcohol 2 0 gm Spenn oil 1 0 gmv Decyl ester of oleic acid 5.0 gm Paraffin all 1.0 gm Distilled water 87.99 gm 100.0 gm

Production:

The micronized active ingredient was suspendedwith an immersion homogenizer in the fatty phase at 70C, and the suspension was emulsified into'water of thesame temperature. The emulsion was cooled to room temperature. 7 i I EXAMPLE F Foam aerosol with 0.01 percent of fluocinolone-acetonide-Z l -isonicotinate Composition:

One container comprises:

Fluocinolone-acetonide-Zl-isonicotinate 0.0025 gm Glycerin 1.0 gm lsopropyl myristate 0.3 gm Cetylstearyl alcohol 0.45 gm Na cetylstearylsulfate 0.05 gm Methyl p-hydroxy-benzoate 0.025 gm Distilled water 20.1725 gm Difluorodichloromethane/tetrafluorodichloroethane 60 40 3.0 gm 25.0 gm Production:

The melt of isoproypl myristate with cetylstearyl alcohol and sodium 'cetylstearyl sulfate was emulsified into the aqueous solution of methyl p-hydroxybenzoate at C. It was cooled to room temperature and the suspension of the micronized fluocinoloneacetonide-Zl-isonicotinate in' glycerin was added. The emulsion was filled into aerosol containers. The latter were sealed by a disk valve. Subsequently, the propellant gas mixture was pressed into it by means of pressure filling and it was homogeneously distributed in the emulsion by shaking. Finally, the valves were equipped with foam dispensers.

EXAMPLE G Tincture with 0.04 percent of fluocinolone-acetonide-Zl-isonicotinate, 0.5 percent of hexachlorophene and 0.02 percent vitamine-E-acetate Composition:

ml of tincture comprise:

Fluocinolone-acetonide-Z 1 -isonicotinate 0.04 gm Hexachlorophene 0.5 gm Vitamin-E-acetate 0.02 gm 96% Ethanol 58.54 gm Distilled water 30.0 gm

The active ingredients were dissolved successively in ethanol. Then the water was added and the solution was filtered.

EXAMPLE H Eye drops with 0.01 percent of fluocinolo'ne-acetonide-Z l -benzofuranate, 0.07

percent of polymyxine-B-sulfate, 0.6 percent of oxytetracyclin HCl and 0.07 percent of 2-- -(5,6,7,8-tetrahydro-l-naphthylamino)2-imidazoline- HCl Composition:

Fluocinolone-acetonide-Z 1 -benzofuranate 0.01 gm Polymyxine-B-sulfate 0.07 gm Oxytetracycline HCl 0.6 gm 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2- imidazoline HCl' 0.07 gm Aerosil 0.05 gm Eye vaseline 27.5 gm Wool fat 2.5 gm lsopropyl myristate 34.6 gm Paraffin oil, viscous 20.7 gm Paraffin oil, fluid 13.9 gm 100.0 gm

Production:

Into the agglomerate-free suspension of the micronized active ingredients and Aerosil in a mixture of isopropyl myristate with paraffin oil was emulsified the warm melt (65C) of the eye vaseline with wool fat with Table I clearly shows that the esters of formula I are 2.2 to 5.5 times more active than fluocinolone acetonide when administered parenterally in single equimolar doses.

an immersion homogenizer. Subsequently the mixture B. Glucocorticoid Activity was cooled to room temperature while stirring slowly. In order to determine the glucocorticoid activity, substances A and B were compared with regard to their PHARMACOLOGICAL DATA total activity, obtained when administered in one por- A. Antiphlogistic Activity tion of equimolar doses, with the activity of the unes-- The antiphlogistic activity was determined as anti- 0 terified fluocinolone-acetonide. The liver glycogen test exudative effects on egg albumin edema in the rats was carried out as described in Arzneimittelforschung, hind paw. It was determined by the total activity ob- VOL 3, p g 538 For the tests, male ra s With tainable after a single subcutaneous administration of an average weight of 80 gm at the beginning of the. tests imolar do were used. On the first day of the tests, the substances In order to determine the antiphlogistic activity, the were given as two single injections into the muscles of following compounds were tested and compared with both hind legs. A 10 percent solution of ethanol in a 0.9 the unesterified fluocinolone-acetonide. percent sodium chloride solution (volume per volume) A Fluocinolone-acetonide-Z1 -isonicotinate was used as solvent vehicle. The control animals got the B Fluocinolone-acetonide-Z1-benzofuranate corresponding quantity of the solvent (1.0 ml per 100 C Fluocinolone-acetonide-Zl-nicotinate gm). The difference between the average glycogen val-- D Fluocinolone-acetonide-Zl-l-menthoxy-acetate. ues of the animals treated with steroids and the control The edema was provoked and measured as described group, simply treated with the solvent, was measured in in Arzneimittelforschung, Vol. 13, page 588 (1963). intervals of 24 hours after the single administration of For the tests, male FW-49 rats weighing about 120-1- substance in the rats, all fasting 24 hours before the gm at the beginning of the test were used. The sub- 25 withdrawal of liver. The average values for the glycostances were injected subcutaneously in one portion as gen increase served as approaching value for the activa microcrystalline suspension in a solution consisting ity integral on the single days following administration, 10 percent of ethanol in a 0.9 percent sodium chloride until the end of the activity in comparison to the consolution at a volume of 0.5 ml/lOO gm of animal. The trol animals.

'0H'T'T'FXEITETTI'W' Increase olliver glycogen compared to control animals by mg.m. 0t glycogen/gm. of liver Dose, aite mg.n1./ Total Relative Substance kg. 24hrs. 48 hrs. 72 hrs. 96 hrs. 120 hrs. activity activity 23.6 0.3 Fluocinolone-acetonide. 1.0 {n 12 12 1.0

. s; 0.9 1.4 32.5 24.7 A 1. 23 {n 12 12 2.4

s} 4. 2 4. 4 31.9 37.4 B 1. 32 {n 12 12 3.8

Glycogen increasein mg.m./gm. of liver.

control animals received corresponding quantities of the carrier liquid. The edema was induced 3, 7, 23, 47, 95 hours after the one-dose administration of the substance and, in case of longer lasting activity, at further 24 hours intervals. For the animals treated with the substance as well as to the control animals, the determination of the reduction of the swelling used the values obtained after 60 minutes after the provocation of the edema.

By provoking edema at various periods after the administration of the substance being tested, points on a curve were obtained whose integral expressed the overall activity of the said products at equimolar doses. The activity integrals calculated from the individual results and the relative activity resulting therefrom are reported in Table I.

TABLE I Anti-exudative effect Substance Dosage in activity relative mgm/kg integral effect Fluocinoloneacetonide 0.25 937 1.0 A 0.308 2655 2.8 B 0.33 5139 5.5 C 0.308 3072 3.3 D 0.358 2048 v 2.2 Fluocinoloneacctonidc 0.5 1904 1.0 A 0.615 5967 3.1 B 0.66 8393 4.4 C 0.616 4120 2.2 D 0.716 5238 2.8

Table II shows that esters A and B are 2.5 and 3.8 times more active than fluocinolone-acetonide in its total gluconeogenetic action obtainable after a single intramuscular injection of equimolar doses. The increase of the total action of the ester, opposite to that of fluocinolone-acetonide, is achieved mainly by prolonged duration of activity, corresponding to the determination of the antiphlogistic effect.

Various modifications of the compositions and method of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only as defined in the appended claims.

We claim: 1. An ester of fluocinolone-acetonide of the formula CHzO-CO-Jt wherein R is selected from the group consisting of pyridine-3, pyridine-4, benzofuran-Zor l-methoxymethyl.

2. The compound of claim 1 which is fluocinoloneacetonide-2 l-nicotinate.

3. The compound of claim 1 which is fluocinclone- 5. The compound of claim 1 which is fluocinoloneacetonide-Zl-isonicotinate. acetonide-Zl l-methoxy-acetate.

4. The compound of claim 1 which is fluocinoloneacetonide-Zl-benzofuranate. V 

2. The compound of claim 1 which is fluocinolone-acetonide-21-nicotinate.
 3. The compound of claim 1 which is fluocinolone-acetonide-21-isonicotinate.
 4. The compound of claim 1 which is fluocinolone-acetonide-21-benzofuranate.
 5. The compound of claim 1 which is fluocinolone-acetonide-21 1-methoxy-acetate. 